Inborn Errors of Metabolism Flashcards

1
Q

Describe alkaptonuria.

A
  • it’s an autosomal recessive condition
  • it is a homogentisic acid oxidase deficiency
  • the urine turns black on standing (and alkalinisation)
  • present with black ochrontic pigmentation of cartilage & collagenous tissue
  • also have arthritis
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2
Q

Describe cystinuria.

A
  • it is an autosomal recessive condition
  • occurs in 1:7,000 poeple
  • there is defective transport of cystine and dibasic amino acids through epithelial cells of the renal tubule and intestinal tract
  • cystine has low solubility, so we end up with formation of calculi in renal tract
  • COLA or COAL
  • mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19) cause this condition
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3
Q

Describe albinism.

A

You can be tyrosinase negative or positive.

TYROSINASE NEGATIVE:

  • Type 1a - complete lack of enzyme activity due to production of inactive tyrosinase
  • Type 1b - reduced activity of tyrosinase

TYROSINASE POSITIVE:
Type II
- AR, biosynthesis of melanin reduced in skin hair and eyes
- most individuals do acquire a small amount of pigment with age

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4
Q

Describe pentosuria.

A

A condition where you 1-4g pentose sugar L-xylulose daily (reducing sugar).

It is benign, and almost exclusively only found in Ashkenazi Jews of Polish-Russian extraction (1:2,500 births).

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5
Q

What are the features of the one gene - one enzyme concept?

A
  • all biochemical processes in all organisms are under genetic control
  • these biochemical processes are resolvable into a series of stepwise reactions
  • each biochemical reaction is under the ultimate control of a different single gene
  • mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction
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6
Q

What are the features of the molecular disease concept?

A
  • brought about with the help of work on haemoglobin in sickle cell disease
  • found direct evidence that human gene mutations actually produce an alteration in the primary structure of proteins
  • inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered
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7
Q

List some different mechanims of inheritance.

A
  • Autosomal recessive
  • Autosomal dominant
  • X-linked
  • Codominant
  • Mitochondrial
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8
Q

Expand on the autosomal recessive mechanism of inheritance.

A
  • both parents carry a mutation affecting the same gene
  • 1 in 4 risk each pregnancy
  • consanguinity increases risk of autosomal recessive conditions
  • examples: Cystic fibrosis, sickle cell disease
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9
Q

Expand on the autosomal dominant mechanism of inheritance.

A
  • these are rare in IEMs

- examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia

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10
Q

Expand on the x-linked mechanism of inheritance.

A
  • it’s characterised by carrier females passing on condition to their affected sons
  • there is no male to male transmission
  • female carriers may manifest condition – lyonisation (random inactivation of one of the X chromosomes)
  • X-linked dominant : fragile X
  • X-linked recessive: haemophilia, Fabry’s disease
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11
Q

Expand on the codominant mechanism of inheritance.

A
  • where two different versions (alleles) of a gene are expressed, and each version makes a slightly different protein
  • both alleles influence the genetic trait or determine the characteristics of the genetic condition
  • example: ABO Blood group, α1AT
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12
Q

Expand on the mitochondrial mechanism of inheritance.

A

Mitochondrial DNA is inherited exclusively from the mother.

  • only the egg contributes mitochondria to the developing embryo
  • thus, only females can pass on mitochondrial mutations to their children; fathers do not pass these disorders to their daughters or sons
  • however, it affects both male and female offspring
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13
Q

How is mitochondrial inheritance determined?

A

The distribution of affected mitochondria determines the presentation.

It’s also found that high energy-requiring organs are more frequently affected.

There’s a current debate on three parent babies to overcome this.

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14
Q

What are some features of inborn error of metabolism?

A
  • inborn errors of metabolism are also known as inherited metabolic disease (IMD)
  • they are individually rare (1:10,000 - 1:500,000)
  • collectively, they present a sizeable problem but they’re cumulatively frequent and account for approximately 42% of deaths within the first year of life
  • they make a significant contribution to the 1% of children of school age with physical handicap and the 0.3% with severe learning difficulties
  • screening programmes are availabel, specifically for newborns
  • there are signs that are important to recognise in a sick neonate
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15
Q

What are the WHO criteria for a good screening test?

A
  • the condition screened for should be an important one
  • there should be an acceptable treatment for patients with the disease
  • facilities for diagnosis and treatment should be available
  • there should be a recognised latent or early symptomatic stage
  • there should be a suitable test or examination which has few false positives -specificity - and few false negatives - sensitivity
  • test or examination should be acceptable to the population
  • cost, including diagnosis and subsequent treatment, should be economically balanced in relation to expenditure on medical care as a whole
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16
Q

In the UK, what do we look for in newborn blood spot screening?

A

Initial National programme:

  • PKU (Phenylketonuria )
  • Congenital hypothyroidism

It’s been extended to include:

  • Cystic fibrosis
  • MCADD
  • Haemoglobinopathies

From 2015, the screening in England expanded to include four additional conditions:

  • Maple syrup urine disease (MSUD)
  • Homocystinuria (pyridoxine unresponsive) (HCU)
  • Isovaleric acidaemia (IVA)
  • Glutaric aciduria type 1 (GA1)
17
Q

How would you take blood spots for a screen?

A

You would prick the heel fof a newborn and get blood samples (spots) from there.

The samples should be taken on day 5 (day of birth is day 0).

All four circles need to be completely filled with a single drop of blood which soaks through to the back of the Guthrie card.

18
Q

Describe the presentatio of IEM.

A

Neonatal presentation is often acute.

It’s often caused by defects in energy metabolism (so will present rapidly):

  • Maple syrup urine disease
  • Tyrosinaemia
  • OTC (urea cycle defect)

Adult:

  • Wilson’s
  • Haemochromatosis
19
Q

Describe neonates with IEM?

A

Most are born at term with normal birthweight and no abnormal features.

The symptoms appear frequently in the first week of life when starting full milk feeds.

Some clues for IEMs:

  • Consanguinity
  • FH of similar illness in sibs or unexplained deaths
  • Infant who was well at birth but starts to deteriorate for no obvious reason
20
Q

What would be the classical representation of an IEM?

A

With a full-term pregnency, the symptoms are very non-specific.

Symtoms, can be non-specific…:

  • Poor feeding
  • Lethargy, Vomiting
  • Hypotonia
  • Fits

…or specific:

  • Abnormal smell (sweet, musty, cabbage-like)
  • Cataracts
  • Hyperventilation secondary to metabolic acidosis
  • Hyponatraemia and ambiguous genitalia
  • Neurological dysfunction with respiratory alkalosis
21
Q

What are some other clinical scenarios that may occur with IEMs?

A

BIOCHEMICAL ABNORMALITIES:

  • Hypoglycaemia
  • Hyperammonaemia
  • Unexplained metabolic acidosis / ketoacidosis
  • Lactic acidosis

CLINICAL:

  • Cognitive decline
  • Epileptic encephalopathy
  • Floppy baby
  • Exercise intolerant
  • Cardiomyopathy
  • Dysmorphic features
  • SUDI
  • Fetal hydrops
22
Q

List some routine laboratory investigations.

A
  • Blood gas analysis
  • Blood glucose
  • Plasma ammonia
23
Q

List some specialist laboratory investigations.

A
  • Plasma amino acids
  • Urinary organic acids + orotic acid
  • Blood acyl carnitines
  • Blood lactate and pyruvate
  • Urinary glycosaminoglycans
  • Plasma very long chain fatty acids
24
Q

List some confirmatory laboratory investigations.

A

Enzymology

  • Red cell galactose-1-phosphate uridyl transferase
  • Lysosomal enzyme screening

Biopsy (muscle, liver)

Fibroblast studies

Complementation studies

Mutation analysis – whole genome sequencing